Polymorphonuclear (PMN) leukocytes are critical in the innate immune response against pathogens. Staphylococcus aureus (SA) is among the most common nosocomial infections and the most frequent cause of non-healing skin wounds. PMN recruitment and abscess formation in cutaneous wounds is a hallmark of these infections and is required for bacterial clearance. However, the increasing emergence of biofilm forming antibiotic-resistant strains such as methicillin resistant SA (MRSA) has complicated their treatment and created a serious public health threat. For instance, MSRA involvement in skin and soft tissue infections increased from 4% to 42% between 2000 and 2005 and remains high. Published data from our laboratory indicates that strategic manipulation of the inflammatory response of PMN at the site of a cutaneous wound suppresses infection and improves the efficiency of non-scar healing. These studies employ non- invasive whole animal fluorescence imaging of transgenic mice expressing EGFP-PMN. This methodology provides a real-time multiparameter readout of the dynamic changes in PMN recruitment and lifetime, SA burden, and wound closure. We propose to investigate three distinct mechanisms that act in concert to recruit PMN for host defense in SA infected tissue, including: (1) a robust and sustained mobilization of PMN from the bone marrow, (2) a prolonged in vivo survival of PMN within the abscess, and (3) trafficking of ckit+ hematopoietic stem and progenitor cells (HSPC) that proliferate and differentiate into mature PMN within the wound. The central hypothesis governing this proposal is that PMN and HSPC recruitment and function in the abscess can be engineered to optimize clearance of microbial infections and prevent aberrant inflammation that delays normal tissue healing. A translational goal will be implementation of a hydrogel delivery system to guide the innate immune response for improving resolution of a persistent SA infection in a mouse model of tissue injury.